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The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3beta and tumor growth in a BT474 tumor xenograft model in mice.

Structural analogs of leukotriene B 4 (LTB 4 ) were designed using a preferred conformation of LTB 4 (1). Appending an aromatic ring scaffold between LTB 4 carbons 7 and 11 led to quinoline analogs (3) and (1)5. A similar modification to the LTB 74 structure between carbons 7 and 9 led to the pyridine analogs (41) and (46). The compounds of this study were evaluated in receptor binding assays using [ 3 H]LTB 4 and intact human DMSO differentiated U-937 cells. The first analog prepared, quinoline (3), displayed moderate potency in the LTB 4 receptor binding assay (K i =0.9 μM). Modification of (3) by appending an aromatic ring between carbons 2 and 4 of the acid side chain produced a dramatic increase in receptor binding (15, K i =0.01 μM); a further improvement in receptor binding was achieved in the pyridine series (e.g., (41); K i =0.001 μM). The LTB 4 receptor agonist/antagonist activity of the test compounds was determined using a functional assay that relies upon intracellular calcium mobilization induced by LTB 4 . Of the analogs prepared in this report only 3-[2-[6-[3-(3-butoxyphenyl)-3-hydroxypropyl]pyridin-2-yl]-1-hydroxyethyl]benzoic acid (47) demonstrated LTB 4 receptor antagonist activity

AKT inhibitors containing an imidazopyridine aminofurazan scaffold have been optimized. We have previously disclosed identification of the AKT inhibitor GSK690693, which has been evaluated in clinical trials in cancer patients. Herein we describe recent efforts focusing on investigating a distinct region of this scaffold that have afforded compounds (30 and 32) with comparable activity profiles to that of GSK690693.

The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.